This invention relates to a formulation of a therapeutic agent such as insulin, that is suitable for administration to the lung, and that has good stability.
There is now widespread interest in the formulation of therapeutic agents for inhalation. In particular, many efforts have been made to formulate suitable therapeutic agents as dry powders for delivery via inhalers.
Typically, the formulations are produced by drying the active agent in the presence of certain excipients, such as polysaccharides or citrate, to enhance stability during the drying process or in storage.
Insulin is a typical example of a therapeutic agent that can be administered to the lung, by inhalation. As a commercial product, insulin is generally provided in suspension or a solution of low concentration, as a hexamer complexed with zinc. Refrigeration is necessary, in order to maintain the stability of such a formulation. Crystalline Zn insulin is stable at neutral pH. The dry powder also requires refrigeration.
CA-A-2136704 discloses a product obtained by spray-drying a medicinal substance such as insulin (among many others) and a carrier. Example 4 discloses spray-drying a clear solution of human insulin, soya bean lecithin and lactose.
WO-A-9735562 again discloses spray-drying a solution of insulin and a polysaccharide. The aim of this combination is to achieve the preferred size range of spray-dried microparticles, for good lung deposition. In Examples 1 and 3, the insulin solution for spray-drying, prior to combination with polysaccharide, is prepared by dissolving zinc insulin in HCl, and then adding NaOH, to pH 7.2. The solutions for spray-drying respectively contain 25 and 6 mg/ml insulin and at least 5.5/7.2% NaCl, based on the combined weight of insulin plus salt.
WO-A-9524183 is directed primarily to a dry powder that comprises insulin and a carrier material, typically a saccharide, in the form of an amorphous powder of microparticles obtained by spray-drying. In addition, the Experimental section compares the properties of such microparticles with and without a saccharide excipient. The insulin solution for spray-drying is prepared by dissolving Zn-insulin in citrate buffer, to pH 6.7xc2x10.3, to a solids content of 7.5 mg/ml. The powder is held in a container at 10% RH.
The formulation without saccharide has considerably lower bioavailability than those with saccharide. For various reasons, this experiment cannot be reproduced: citrate is a buffer at pH 3.0-6.2, and not at pH 6.7; crystalline insulin will not dissolve in pH 6.2 citrate buffer before or after adjustment to pH 7.4 with NaOH; in any case, no alkali addition is specified.
The presence of citrate in dry powder formulations was believed to be necessary to enhance the stability of the final product (Drug Development and Industrial Pharmacy 1984; 10(3):425-451). However, in many cases, the high citrate concentration dilutes the amount of active agent in the initial feedstock, resulting in low amounts of active for drying.
After the date of this invention, Pikal and Rigsbee, Pharm. Rev. 14(10):1379-87 (1997), reported that freeze-dried amorphous insulin was significantly more stable than crystalline insulin at corresponding water contents from 0 to 15% w/w. The mechanism was unclear, but may have been due to configurational differences between the amorphous and crystalline states, the reactive parts of protein being in closer proximity in the later. The formulation reported by Pikal and Rigsbee contains no salt, because such low concentrations of insulin (c. 0.5% w/v) are used that manipulation of the pH is unnecessary.
WO95/23613 discloses a spray-dried DNase formulation. The spray-dried product is in a crystalline form, due primarily to a high concentration of salt. It is stated that high concentrations of salt increases the dispersibility qualities of the final product. In Example 1, the final product contains 60% salt compared with 30% of the DNase.
In summary, the prior art discloses various results of interest but of uncertain commercial significance. None of the procedures described above gives a pure insulin product that is stable, or uses a sufficiently concentrated solution for spray-drying, to be suitable as a commercial procedure. The most effective procedures invariably suggest that co-spray-drying of insulin and, say, a saccharide is necessary for best results.
The present invention is based on the surprising discovery that it is possible to spray-dry a therapeutic agent at higher (and therefore commercially useful) concentrations than have been used previously, without the concomitant production of an undesirable high concentration of salt or other excipients. Such formulations show no substantial loss of activity after the drying process and have extended stability, by comparison with pre-spray-dried preparations. This discovery is of value for all therapeutic agents, in particular proteins and peptides to be administered by spray-drying a substantially pure solution of a therapeutic agent, consist essentially only of the agent. In a preferred embodiment, the microparticles consist essentially only of insulin and NaCl salt. Such microparticles may be held in a container at greater than 10% RH, and thus essentially at ambient humidity. The insulin microparticles are obtainable by dissolving Zn-insulin in acid, adding alkali to give an insulin solution, e.g. to a pH above 7, and spray-drying the insulin solution (which also contains a salt formed as a result of the dissolution process, or a buffer)
Preferably, the microparticles are non-crystalline/amorphous
As indicated above, microparticles of the invention xe2x80x9cconsist essentiallyxe2x80x9d of the therapeutic agent. This term is used herein to indicate that they are substantially free of polysaccharide, or buffer salt, e g citrate, since none is necessary. In general, there will be no polysaccharide present at all, although an amount of up to, say 10% by weight may be tolerated. The absence of polysaccharide has the advantage that a given unit dosage, e.g. a particle, contains essentially only the intended active component. This is an important consideration, for a drug that may be required in large amounts. Another advantage is the avoidance of delivering unnecessary material to a subject. A further advantage is that consistent dosing of the therapeutic agent is facilitated, this is especially important where there is a narrow therapeutic window.
The absence of buffer salt is desirable as it allows a more concentrated feedstock solution of the active agent to be spray-dried resulting in significant cost savings and providing a more commercial-scale process to be adopted.
The term xe2x80x9csubstantially purexe2x80x9d is used herein to indicate that the feedstock solution to be spray-dried comprises primarily only therapeutic agent and solvent. Again, as described above, there may be minor amount of solids other than the active agent, but this has no significant effect on the eventual stability of the product.
Insulin microparticles of the invention may include components that are produced during the successive addition of acid and alkali, in preparation of the feedstock, e.g. a salt. For example, NaCl is formed if the acid and alkali are respectively HCl and NaOH. It has been found that the presence of NaCl apparently has no stabilising effect. Indeed, stability may be greater with reduced amounts of salt, again allowing a more concentrated feedstock to be used.
Typically, the solution for spray-drying may contain less than 4% by weight of salt, by weight of total solids. The salt content is based on theoretical considerations, by titration to pH 7. More particularly, this value is calculated by consideration of the molar quantities of the ions added during dissolution. The solution may contain any desired amount of the therapeutic agent, e.g. more than 20, 30 or 50 mg/ml, often up to 100 or 200 mg/ml.
As indicated above, successive addition of acid and alkali apparently destroys the crystalline form of Zn insulin. Zn may dissociate from the hexameric complex but need not be removed. Accordingly, Zn may be present in the microparticles. If desired, this or any other component, other than the therapeutic agent, may be removed, using any suitable technique known to those of skill in the art. In a preferred embodiment for insulin, the Zn is removed from solution prior to spray-drying. This may be achieved by diafiltering the solution according to methods known in the art. The Zn-free insulin may have greater stability than the Zn-containing product. Moisture may also be present.
As disclosed in more detail in WO-A-9218164, WO-A-9408627 and other Andaris publications, the conditions of spray-drying can be controlled so that microparticles having a defined size range, e.g. 0.1 to 50 xcexcm, can be obtained. The mass median particle size is preferably 1 to 10 xcexcm, when the product is intended for administration by inhalation.
The microparticles (microcapsules) obtained by spray-drying may be solid or hollow Further, the surface may be smooth or xe2x80x9cdimpledxe2x80x9d; a dimpled surface may be beneficial for inhalation.
The microparticles have good stability and may be maintained as such, i.e. as a dry powder, in a container. During storage or in formulation, they may be mixed with any suitable pharmaceutical agents, carriers, bulking agents etc, and they may be processed by any technique desired to give a product having the properties intended for the ultimate therapeutic use. In particular, the formulation of particles for formulations that can be delivered to the lung, e.g. using a metered dose or dry powder inhaler, are known to those skilled in the art.
The nature of the container is not critical. For example, it may be a glass jar or plastics box. It merely defines a storage environment within which, unlike the prior art and as evidenced below, there is no need to remove moisture or otherwise to control the conditions.
The therapeutic agent may be any protein or peptide having a desired therapeutic effect. Included within the definition of proteins and peptides are functional derivatives, such as glycoproteins. Typical examples of proteins that may be used include enzymes, hormones and blood plasma products. DNase and trypsin are specific examples. Others include growth hormone, calcitonins, interferons, interleukin-1 receptor and low molecular weight heparin.
The therapeutic agent may in particular be any of those described in WO-A-9632149. Insulin that is used in the invention may be of any suitable form. It may be, for example, bovine or human insulin. Results that have been obtained, regarding the stability of bovine insulin, apparently apply also to human insulin.
The following Examples illustrate the invention.